Linezolid - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Linezolid is an antibacterial drug [ see Microbiology ].

12.2 Pharmacodynamics In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single linezolid 600 mg dose via a 1 hour IV infusion, a single linezolid 1,200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control.

At both the 600 mg and 1,200 mg linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.

12.3 Pharmacokinetics The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8.

Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.

Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults Dose of Linezolid C max mcg/mL C min mcg/mL T max hrs AUC AUC for single dose = AUC 0–∞ ; for multiple dose = AUC 0–τ mcg∙h/mL t 1/2 hrs CL mL/min C max = Maximum plasma concentration; C min = Minimum plasma concentration; T max = Time to C max ; AUC = Area under concentration-time curve; t 1/2 = Elimination half-life; CL = Systemic clearance 400 mg tablet single dose Data dose-normalized from 375 mg 8.10 --- 1.52 55.10 5.20 146 every 12 hours 11.00 3.08 1.12 73.40 4.69 110 600 mg tablet single dose 12.70 --- 1.28 91.40 4.26 127 every 12 hours 21.20 6.15 1.03 138.00 5.40 80 600 mg IV injection Data dose-normalized from 625 mg, intravenous dose was given as 0.5-hour infusion. single dose 12.90 --- 0.50 80.20 4.40 138 every 12 hours 15.10 3.68 0.51 89.70 4.80 123 600 mg oral suspension single dose 11.00 --- 0.97 80.80 4.60 141 Figure 1.

Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16) Absorption Linezolid is extensively absorbed after oral dosing.

Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%.

Therefore, linezolid may be given orally or intravenously without dose adjustment.

Linezolid may be administered without regard to the timing of meals.

The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and C max is decreased by about 17% when high fat food is given with linezolid.

However, the total exposure measured as AUC 0–∞ is similar under both conditions.

Distribution Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues.

The plasma protein binding of linezolid is approximately 31% and is concentration-independent.

The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.

Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid.

The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and the ratio of linezolid in sweat relative to plasma was 0.55 to 1.

Metabolism Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B).

Formation of metabolite A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro.

In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome P450.